Insulin-dependent diabetes is a complex multifactorial disorder characterized by loss or dysfunction of β-cells. Pancreatic β-cells differ in size, glucose responsiveness, insulin secretion and precursor cell potential; understanding the mechanisms that underlie this functional heterogeneity might make it possible to develop new regenerative approaches. Here we show that Fltp (also known as Flattop and Cfap126), a Wnt/planar cell polarity (PCP) effector and reporter gene acts as a marker gene that subdivides endocrine cells into two subpopulations and distinguishes proliferation-competent from mature β-cells with distinct molecular, physiological and ultrastructural features. Genetic lineage tracing revealed that endocrine subpopulations from Fltp-negative and -positive lineages react differently to physiological and pathological changes. The expression of Fltp increases when endocrine cells cluster together to form polarized and mature 3D islet mini-organs. We show that 3D architecture and Wnt/PCP ligands are sufficient to trigger β-cell maturation. By contrast, the Wnt/PCP effector Fltp is not necessary for β-cell development, proliferation or maturation. We conclude that 3D architecture and Wnt/PCP signalling underlie functional β-cell heterogeneity and induce β-cell maturation. The identification of Fltp as a marker for endocrine subpopulations sheds light on the molecular underpinnings of islet cell heterogeneity and plasticity and might enable targeting of endocrine subpopulations for the regeneration of functional β-cell mass in diabetic patients.
Advanced imaging techniques have become a valuable tool in the study of complex biological processes at the cellular level in biomedical research. Here, we introduce a new technical platform for noninvasive in vivo fluorescence imaging of pancreatic islets using the anterior chamber of the eye as a natural body window. Islets transplanted into the mouse eye engrafted on the iris, became vascularized, retained cellular composition, responded to stimulation and reverted diabetes. Laserscanning microscopy allowed repetitive in vivo imaging of islet vascularization, beta cell function and death at cellular resolution. Our results thus establish the basis for noninvasive in vivo investigations of complex cellular processes, like beta cell stimulus-response coupling, which can be performed longitudinally under both physiological and pathological conditions. Adequate release of insulin by pancreatic beta cells in response to changing blood glucose levels is a vital requirement for maintaining glucose homeostasis. Failure to do so is one of the major causes of type 2 diabetes mellitus, the most common metabolic disorder in humans 1 . Under physiological conditions, insulin release is regulated by the complex interplay between glucose and a plethora of additional factors-for example, nutrients, autocrine-paracrine signaling and the continuous input from hormones and neurotransmitters 2 . Beta cells, together with other pancreatic endocrine cell types, are situated within the endocrine pancreas, that is, the islets of Langerhans, which are densely vascularized 3 and abundantly innervated 4 . Pancreatic islets, constituting 1%-2% of the pancreatic volume, are difficult to access for in vivo monitoring because they are deeply embedded and scattered in the exocrine tissue of the pancreas 5 . As a consequence, the majority of functional beta cell studies have so far been conducted in vitro on isolated islets or beta cells. Isolated islets 6 , and especially pancreatic slices 7 , allow functional studies of Author Contributions: S.S., D.N. and A.C. developed the experimental transplantation platform. S.S., D.N., O.C., J.Y., R.D.M., A.P., T.M., M.K., B.L. and A.C. did the experiments. J.W. was responsible for generating the transgenic mice. C.R. was involved in designing the transplantation protocols and writing the manuscript. S.S., D.N., I.B.L. and P.-O.B. were responsible for designing the overall experimental plan and writing the manuscript. P.-O.B. was the originator of the idea of using the anterior chamber of the eye for noninvasive in vivo imaging of pancreatic islet cell biology Reprints and permissions information is available online at http://npg.nature.com/reprintsandpermissions Note: Supplementary information is available on the Nature Medicine website. Laser-scanning microscopy (LSM) of isolated islets and cell preparations has been successfully applied for imaging multiple signaling pathways in the beta cell 6 . However, intravital applications of LSM for studies of beta cell physiology have not been repo...
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